Process for the preparation of thiamphenicol glycinate acetylcysteinate

ABSTRACT

A process for the preparation of thiamphenicol glycinate acetylcysteinate with the formula: IN WHICH THIAMPHENICOL GLYCINATE HYDROCHLORIDE IS MADE TO REACT WITH A STOICHIOMETRIC QUANTITY OF DICYCLOHEXYLAMINE IN DIMETHYLFORMAMIDE, THE STOICHIOMETRIC QUANTITY OF ACETYLCYSTEINE IS ADDED TO THE SOLUTION FILTERED FROM THE PRECIPITATED DICYCLOHEXYLAMMONIUM HYDROCHLORIDE AND THE THIAMPHENICOL GLYCINATE ACETYLCYSTEINATE FORMED IS SEPARATED BY PRECIPITATION WITH A PRECIPITATION AGENT SELECTED FROM THE GROUP CONSISTING OF CHLOROFORM AND ETHYL ETHER.

United States Patent Della Bella et al.

[ 51 Sept. 12, 1972 [54] PROCESS FOR THE PREPARATION OF THIAMPHENICOLGLYCINATE ACETYLCYSTEINATE [72] Inventors: Davide Della Bella, Milan;Mario Portelli, Vicenza; Giorgio Renzi,

Bresso, all of Italy [73] Assignee: Zambon S.p.A., Bresso, Milan,

Italy [22] Filed: June 8,1970

211 App]. No.: 44,614

[30] Foreign Application Priority Data June 7, 1969 Italy ..l7866 A/69[52] US. Cl. ..260/481 R, 424/31 l [5 l] Int. Cl ..C07c 149/20 [58]Field of Search .260/48l C, 482 R, 481 R [56] References Cited UNITEDSTATES PATENTS 3,542,854 11/1970 Teotino ..260/482 PrimaryExaminerLorraine A. Weinberger Assistant Examiner-John F. TerapaneAttorney-Stevens, Davis, Miller & Mosher [5 7] ABSTRACT A process forthe preparation of thiamphenicol glycinate acetyl-cysteinate with theformula:

NHCOCHCM 1 Claim, No Drawings PROCESS FORTHE PREPARATION OFTHIAMPHENICOL GLYCINATE ACETYLCYSTEINATE The present invention relatesto a new process for the preparation ofD(+)threo-l-(p-methylsulphonylphenyl)-2-dichloroacetamide-3-aminoacetoxy-1-propanol acetylcysteinate (thiamphenicol glycinateacetylcysteinate),with the formula:

l,064,970),thiamphenicol glycinate acetylcysteinate is a therapeuticcompound of great use in all those cases in which the infectiveprocesses are accompanied by viscous secretions in that it combines initself the strong mucolyctic action of acetylcysteine and theantibacterial activity of thiamphenicol glycinate. Surprisingly, theantibacterial activity is greater by 20 to 50 percent than that ofthiamphenicol glycinate, according to the stock treated.

According to the known process, thiamphenicol glycinate acetylcysteinateis prepared by reacting thiamphenicol glycinate with acetylcysteine inan organic solvent, preferably methyl alcohol, and drying the solution.

In practice, and in particular when passing to industrial production,this process results in difficult attainment because of the limitedstability of thiamphenicol glycinate which makes its conservation andmanipulation difficult.

It was thus immediately evident that instead of using thiamphenicolglycinate it would have been very convenient to use one of its stableacid addition salts.

However tests conducted in this direction, seeking to make thiamphenicolglycinate hydrochloride react with acetylcysteine according to the usualmethod in an organic solvent and in presence of a tertiary base such aspyridine, trimethylamine, etchave given completely negative orunsatisfactory results from the point of view of the yield.

The object of the present invention is a process which permitsthiamphenicol glycinate acetylcysteinate to be obtained industriallywith high yields. The process consists essentially of makingthiamphenicol glycinate hydrochloride react with dicyclohexylamine in asuitable solvent, eliminating by filtration the dicyclohexylammoniumhydrochloride precipitated and reacting the thiamphenicol glycinate in asolution thus obtained with acetylcysteine.

The thiamphenicol glycinate acetylcysteinate is precipitated from thesolution which contains it by mixing with a precipitation solvent.

Suitable solvents for making the reaction between thaimphenicolglycinate hydrochloride and dicyclohexylamine take place are thosecapable of carrying in solution the thiamphenicol glycinatehydrochloride, dicyclohexylamine, acetylcysteine and thiamphenicolglycinate acetyl-cysteinate, but have a practically zero or minimumsolvent power for dicyclohexylammonium hydrochloride. We have found thata solvent which satisfied all these critical requisites from the pointof view of being able to carry out the process is dimethylformamide. Wehave also found that by working in dimethylformamide as solvent,chloroform and ethyl ether are suitable precipitation agents. Theprecipitation of the final product takes place more rapidly andcompletely by cooling the mixture to 0 C or even lower temperatures.

The dicyclohexylamine is easily recovered by decomposition of thedicyclohexylammonium hydrochloride and recycled. The yields are alwaysbetween and percent.

Thiamphenicol glycinate acetylcysteinate can be used either in aerosolform or by parenteral administration.

An example will now be given of the practical attainment of the processaccording to the present invention with the object of illustrating itwithout limiting the same.

EXAMPLE To a solution of 2 kg (4.45 moles) of D(+)threo-1-(p.methylsulphonyl phenyl)-2-dichloroacetamide-3- aminoacetoxy- 1-propanol hydrochloride, dissolved in 8 liters of dimethylformamide,0.805 Kg (4.45 moles) of dicyclohexylamine are added with mixing.

After 30 minutes of mixing, the precipitated dicyclohexylammoniumchlorohydrate is filtered and washed with 2 liters of dimethylformamide.To the dimethylformamidic solution thus obtained, 0.726 Kg (4.45 moles)of acetylcysteine are added with mixing, and when completely dissolved,28 liters of chloroform are added. The mixture is cooled to 0 C and theprecipitate filtered, which after washing with absolute ethyl alcohol isdried.

2.1 Kg of D(+)threol-(p.methylsulphonyl phenyl)-2-dichloroacetamide-3-aminoacetoxy-1-propanol acetylcysteinate areobtained, equal to a yield of 82 percent.

percent in H O) Analysis: Percent calc=N 7.29 Cl 12.3 ;S 11.12 Percentfound= 7.19; 12.3.; 11.09

What we claim is l. A process for the preparation (if thiamphenicolglycinate acetylcysteinate of the formula:

comprising reacting thiamphenicol glycinate hydrochloride with astoichiometric quantity of dicyclohexylamine in dimethylformamide,adding the stoichiometric quantity of acetylcysteine to the solutionfiltered from the precipitated dicyclohexylammonium chloride, andseparating by precipitation the thus formed thiamphenicol glycinateacetylcysteinate by precipitation with a precipitating agent selectedfrom the group consisting of chloroform and ethyl ether.

